SummaryThe recent IPCC report identifies mineral dust and the associated uncertainties in climate projections as key topics for future research. Dust size distribution in climate models controls the dust-radiation-cloud interactions and is a major contributor to these uncertainties. Observations show that the coarse mode of dust can be sustained during long-range transport, while current understanding fails in explaining why the lifetime of large airborne dust particles is longer than expected from gravitational settling theories. This discrepancy between observations and theory suggests that other processes counterbalance the effect of gravity along transport. D-TECT envisages filling this knowledge gap by studying the contribution of the triboelectrification (contact electrification) on particle removal processes. Our hypothesis is that triboelectric charging generates adequate electric fields to hold large dust particles up in the atmosphere. D-TECT aims to (i) parameterize the physical mechanisms responsible for dust triboelectrification; (ii) assess the impact of electrification on dust settling; (iii) quantify the climatic impacts of the process, particularly the effect on the dust size evolution during transport, on dry deposition and on CCN/IN reservoirs, and the effect of the electric field on particle orientation and on radiative transfer. The approach involves the development of a novel specialized high-power lidar system to detect and characterize aerosol particle orientation and a large-scale field experiment in the Mediterranean Basin using unprecedented ground-based remote sensing and airborne in-situ observation synergies. Considering aerosol-electricity interactions, the observations will be used to improve theoretical understanding and simulations of dust lifecycle. The project will provide new fundamental understanding, able to open new horizons for weather and climate science, including biogeochemistry, volcanic ash and extraterrestrial dust research.

The recent IPCC report identifies mineral dust and the associated uncertainties in climate projections as key topics for future research. Dust size distribution in climate models controls the dust-radiation-cloud interactions and is a major contributor to these uncertainties. Observations show that the coarse mode of dust can be sustained during long-range transport, while current understanding fails in explaining why the lifetime of large airborne dust particles is longer than expected from gravitational settling theories. This discrepancy between observations and theory suggests that other processes counterbalance the effect of gravity along transport. D-TECT envisages filling this knowledge gap by studying the contribution of the triboelectrification (contact electrification) on particle removal processes. Our hypothesis is that triboelectric charging generates adequate electric fields to hold large dust particles up in the atmosphere. D-TECT aims to (i) parameterize the physical mechanisms responsible for dust triboelectrification; (ii) assess the impact of electrification on dust settling; (iii) quantify the climatic impacts of the process, particularly the effect on the dust size evolution during transport, on dry deposition and on CCN/IN reservoirs, and the effect of the electric field on particle orientation and on radiative transfer. The approach involves the development of a novel specialized high-power lidar system to detect and characterize aerosol particle orientation and a large-scale field experiment in the Mediterranean Basin using unprecedented ground-based remote sensing and airborne in-situ observation synergies. Considering aerosol-electricity interactions, the observations will be used to improve theoretical understanding and simulations of dust lifecycle. The project will provide new fundamental understanding, able to open new horizons for weather and climate science, including biogeochemistry, volcanic ash and extraterrestrial dust research.

SummaryCancer is a major clinical, societal and economic burden worldwide and development of novel anti-cancer therapies constitutes a major investment of public and private funds. Despite intense research over decades however, which has led to a much improved understanding of cancer biology, cancer treatment remains a challenge. This is to a large extent due to the genetic heterogeneity of cancer and the ability of cancer cells to escape treatment by constantly undergoing further genetic alterations. During our ERC funded work, we have shown that aberrations in the DNA replication licensing pathway may contribute to the genome plasticity of cancer cells, and appear a common feature of cancer cells. They may however also constitute an Achilles foot, as cancer cells appear more dependent on negative regulators of the licensing system for survival. Cancer cells may therefore be more sensitive than normal cells to compounds targeting this control (inhibition of untimely licensing). We have identified compounds which target the DNA replication licensing inhibitor Geminin. The proposed PoC study will enable us to:
- assess the efficacy and specificity of the identified compounds in cells and preclinical models and study their mechanism of action.
- investigate the potential use of these compounds for studying cell cycle processes.
- assess whether the functional imaging approaches developed under the mother ERC project, which quantify protein-protein interactions within living cells, may constitute a powerful tool for in-cell analysis of novel lead compounds.
The project thus aims to characterize, protect and commercialize novel putative anti-tumor agents as well as the in-cell methods developed for their characterization.

Cancer is a major clinical, societal and economic burden worldwide and development of novel anti-cancer therapies constitutes a major investment of public and private funds. Despite intense research over decades however, which has led to a much improved understanding of cancer biology, cancer treatment remains a challenge. This is to a large extent due to the genetic heterogeneity of cancer and the ability of cancer cells to escape treatment by constantly undergoing further genetic alterations. During our ERC funded work, we have shown that aberrations in the DNA replication licensing pathway may contribute to the genome plasticity of cancer cells, and appear a common feature of cancer cells. They may however also constitute an Achilles foot, as cancer cells appear more dependent on negative regulators of the licensing system for survival. Cancer cells may therefore be more sensitive than normal cells to compounds targeting this control (inhibition of untimely licensing). We have identified compounds which target the DNA replication licensing inhibitor Geminin. The proposed PoC study will enable us to:
- assess the efficacy and specificity of the identified compounds in cells and preclinical models and study their mechanism of action.
- investigate the potential use of these compounds for studying cell cycle processes.
- assess whether the functional imaging approaches developed under the mother ERC project, which quantify protein-protein interactions within living cells, may constitute a powerful tool for in-cell analysis of novel lead compounds.
The project thus aims to characterize, protect and commercialize novel putative anti-tumor agents as well as the in-cell methods developed for their characterization.

Max ERC Funding

150 000 €

Duration

Start date: 2017-07-01, End date: 2018-12-31

Project acronymEpiTrack

ProjectSingle-cell temporal tracking of epigenetic DNA marks

Researcher (PI)Saulius KLIMASAUSKAS

Host Institution (HI)VILNIAUS UNIVERSITETAS

Call DetailsAdvanced Grant (AdG), LS9, ERC-2016-ADG

SummaryOver the past decade, epigenetic phenomena have taken centre stage in our understanding of gene regulation, cellular differentiation and human disease. DNA methylation is a prevalent epigenetic modification in mammals, which is brought about by enzymatic transfer of methyl groups from the S-adenosylmethionine (SAM) cofactor by three known DNA methyltransferases (DNMTs). The most dramatic epigenomic reprogramming in mammalian development occurs after fertilization, whereby a global loss of DNA methylation is followed by massive reinstatement of new methylation patterns, different for each cell type. Although DNA methylation has been extensively investigated, key mechanistic aspects of these fascinating events remain obscure. The goal of this proposal is to bridge the gap in our understanding of how the genomic methylation patterns are established and how they govern cell plasticity and variability during differentiation and development. These questions could only be answered by precise determination of where and when methylation marks are deposited by the individual DNMTs, and how these methylation marks affect gene expression. To achieve this ambitious goal, we will metabolically engineer mouse cells to permit SAM analog-based chemical pulse-tagging of their methylation sites in vivo. We will then advance profiling of DNA modifications to the single cell level via innovative integration of microdroplet-based barcoding, precise genomic mapping and super-resolution imaging. Using this unique experimental system we will determine, with unprecedented detail and throughput, the dynamics and variability of DNA methylation and gene expression patterns during differentiation of mouse embryonic cells to neural and other lineages. This project will give a comprehensive, time-resolved view of the roles that the DNMTs play in mammalian development, which will open new horizons in epigenomic research and will advance our understanding of human development and disease.

Over the past decade, epigenetic phenomena have taken centre stage in our understanding of gene regulation, cellular differentiation and human disease. DNA methylation is a prevalent epigenetic modification in mammals, which is brought about by enzymatic transfer of methyl groups from the S-adenosylmethionine (SAM) cofactor by three known DNA methyltransferases (DNMTs). The most dramatic epigenomic reprogramming in mammalian development occurs after fertilization, whereby a global loss of DNA methylation is followed by massive reinstatement of new methylation patterns, different for each cell type. Although DNA methylation has been extensively investigated, key mechanistic aspects of these fascinating events remain obscure. The goal of this proposal is to bridge the gap in our understanding of how the genomic methylation patterns are established and how they govern cell plasticity and variability during differentiation and development. These questions could only be answered by precise determination of where and when methylation marks are deposited by the individual DNMTs, and how these methylation marks affect gene expression. To achieve this ambitious goal, we will metabolically engineer mouse cells to permit SAM analog-based chemical pulse-tagging of their methylation sites in vivo. We will then advance profiling of DNA modifications to the single cell level via innovative integration of microdroplet-based barcoding, precise genomic mapping and super-resolution imaging. Using this unique experimental system we will determine, with unprecedented detail and throughput, the dynamics and variability of DNA methylation and gene expression patterns during differentiation of mouse embryonic cells to neural and other lineages. This project will give a comprehensive, time-resolved view of the roles that the DNMTs play in mammalian development, which will open new horizons in epigenomic research and will advance our understanding of human development and disease.

Max ERC Funding

2 499 875 €

Duration

Start date: 2017-09-01, End date: 2022-08-31

Project acronymFastBio

ProjectA genomics and systems biology approach to explore the molecular signature and functional consequences of long-term, structured fasting in humans

SummaryDietary intake has an enormous impact on aspects of human health, yet scientific consensus about how what we eat affects our biology remains elusive. To address the complex biological impact of diet, I propose to apply an unconventional, ‘humans-as-model-organisms’ approach to compare the molecular and functional effects of a highly structured dietary regime, specified by the Eastern Orthodox Christian Church (EOCC), to the unstructured diet followed by the general population. Individuals who follow the EOCC regime abstain from meat, dairy products and eggs for 180-200 days annually, in a temporally-structured manner initiated in childhood. I aim to explore the biological signatures of structured vs. unstructured diet by addressing three objectives. First I will investigate the effects of the two regimes, and of genetic variation, on higher-level phenotypes including anthropometric, physiological and biomarker traits. Second, I will carry out a comprehensive set of omics assays (metabolomics, transcriptomics, epigenomics and investigation of the gut microbiome), will associate omics phenotypes with genetic variation, and will integrate data across biological levels to uncover complex molecular signatures. Third, I will interrogate the functional consequences of dietary regimes at the cellular level through primary cell culture. Acute and long-term effects of dietary intake will be explored for all objectives through a two timepoint sampling strategy. This proposal therefore comprises a unique opportunity to study a specific perturbation (EOCC structured diet) introduced to a steady-state system (unstructured diet followed by the general population) in a ground-breaking human systems biology type of study. This approach brings together expertise from genomics, computational biology, statistics, medicine and epidemiology. It will lead to novel insights regarding the potent signalling nature of nutrients and is likely to yield results of high translational value.

Dietary intake has an enormous impact on aspects of human health, yet scientific consensus about how what we eat affects our biology remains elusive. To address the complex biological impact of diet, I propose to apply an unconventional, ‘humans-as-model-organisms’ approach to compare the molecular and functional effects of a highly structured dietary regime, specified by the Eastern Orthodox Christian Church (EOCC), to the unstructured diet followed by the general population. Individuals who follow the EOCC regime abstain from meat, dairy products and eggs for 180-200 days annually, in a temporally-structured manner initiated in childhood. I aim to explore the biological signatures of structured vs. unstructured diet by addressing three objectives. First I will investigate the effects of the two regimes, and of genetic variation, on higher-level phenotypes including anthropometric, physiological and biomarker traits. Second, I will carry out a comprehensive set of omics assays (metabolomics, transcriptomics, epigenomics and investigation of the gut microbiome), will associate omics phenotypes with genetic variation, and will integrate data across biological levels to uncover complex molecular signatures. Third, I will interrogate the functional consequences of dietary regimes at the cellular level through primary cell culture. Acute and long-term effects of dietary intake will be explored for all objectives through a two timepoint sampling strategy. This proposal therefore comprises a unique opportunity to study a specific perturbation (EOCC structured diet) introduced to a steady-state system (unstructured diet followed by the general population) in a ground-breaking human systems biology type of study. This approach brings together expertise from genomics, computational biology, statistics, medicine and epidemiology. It will lead to novel insights regarding the potent signalling nature of nutrients and is likely to yield results of high translational value.

Max ERC Funding

1 500 000 €

Duration

Start date: 2017-06-01, End date: 2022-05-31

Project acronymHETEROPOLITICS

ProjectRefiguring the Common and the Political

Researcher (PI)Alexandros KIOUPKIOLIS

Host Institution (HI)ARISTOTELIO PANEPISTIMIO THESSALONIKIS

Call DetailsConsolidator Grant (CoG), SH5, ERC-2016-COG

SummaryHeteropolitics is a project in contemporary political theory which purports to contribute to the renewal of political thought on the ‘common’ (communities and the commons) and the political in tandem. The common implies a variable interaction between differences which communicate and collaborate in and through their differences, converging partially on practices and particular pursuits. The political pertains to processes through which plural communities manage themselves in ways which enable mutual challenges, deliberation, and creative agency.
Since the dawn of the 21st century, a growing interest in rethinking and reconfiguring community has spread among theorists, citizens and social movements (see e.g. Esposito 2013; Dardot & Laval 2014; Amin & Roberts 2008). This has been triggered by a complex tangle of social, economic and political conditions. Climate change, economic crises, globalization, increasing migration flows and the malaise of liberal democracies loom large among them.
These issues are essentially political. Rethinking and refiguring communities goes hand in hand thus with rethinking and reinventing politics. Hence ‘hetero-politics’, the quest for another politics, which can establish bonds of commonality across differences and can enable action in common without re-enacting the closures of ‘organic’ community or the violence of transformative politics in the past.
Heteropolitics will seek to break new ground by combining an extended re-elaboration of contemporary political theory with a more empirically grounded research into alternative and incipient practices of community building and self-governance in: education; the social economy; art; new modes of civic engagement by young people; new platforms of citizens’ participation in municipal politics; network communities, and other social fields (Relevant cases include Sardex, a community currency in Sardinia; Barcelona en Comú, a citizens’ platform governing the city of Barcelona, etc.)

Heteropolitics is a project in contemporary political theory which purports to contribute to the renewal of political thought on the ‘common’ (communities and the commons) and the political in tandem. The common implies a variable interaction between differences which communicate and collaborate in and through their differences, converging partially on practices and particular pursuits. The political pertains to processes through which plural communities manage themselves in ways which enable mutual challenges, deliberation, and creative agency.
Since the dawn of the 21st century, a growing interest in rethinking and reconfiguring community has spread among theorists, citizens and social movements (see e.g. Esposito 2013; Dardot & Laval 2014; Amin & Roberts 2008). This has been triggered by a complex tangle of social, economic and political conditions. Climate change, economic crises, globalization, increasing migration flows and the malaise of liberal democracies loom large among them.
These issues are essentially political. Rethinking and refiguring communities goes hand in hand thus with rethinking and reinventing politics. Hence ‘hetero-politics’, the quest for another politics, which can establish bonds of commonality across differences and can enable action in common without re-enacting the closures of ‘organic’ community or the violence of transformative politics in the past.
Heteropolitics will seek to break new ground by combining an extended re-elaboration of contemporary political theory with a more empirically grounded research into alternative and incipient practices of community building and self-governance in: education; the social economy; art; new modes of civic engagement by young people; new platforms of citizens’ participation in municipal politics; network communities, and other social fields (Relevant cases include Sardex, a community currency in Sardinia; Barcelona en Comú, a citizens’ platform governing the city of Barcelona, etc.)

SummaryThe aim of the HYDROPHO-CHEAP project is to optimize, protect, and commercialize a recently developed methodology that allowed us to achieve “tailor-made” control of the wettability of polymer surfaces, rendering them super water-repellent.
What makes our methodology highly innovative is the fast and cheap fabrication process, and most importantly the potential of implementing it in real-life environments. With this unique method we can fabricate ‘superhydrophobic islands’ (with a spatial resolution of 100 μm in the horizontal plane) of any shape i.e. dots, stripes, polygons and interconnected shapes, in any combination. Such functional surfaces can be produced in a single and fast fabrication step, without applying any hydrophobization top coating since we process an inherently hydrophobic material.
We plan to demonstrate the capabilities that our method can offer to specific applications (microfluidic chips, fog harvesting, low flow friction surfaces) that we identified as the most prominent, protect the intellectual property that we have produced through our research and to find the optimum route-to-market in order to commercialize our research results.

The aim of the HYDROPHO-CHEAP project is to optimize, protect, and commercialize a recently developed methodology that allowed us to achieve “tailor-made” control of the wettability of polymer surfaces, rendering them super water-repellent.
What makes our methodology highly innovative is the fast and cheap fabrication process, and most importantly the potential of implementing it in real-life environments. With this unique method we can fabricate ‘superhydrophobic islands’ (with a spatial resolution of 100 μm in the horizontal plane) of any shape i.e. dots, stripes, polygons and interconnected shapes, in any combination. Such functional surfaces can be produced in a single and fast fabrication step, without applying any hydrophobization top coating since we process an inherently hydrophobic material.
We plan to demonstrate the capabilities that our method can offer to specific applications (microfluidic chips, fog harvesting, low flow friction surfaces) that we identified as the most prominent, protect the intellectual property that we have produced through our research and to find the optimum route-to-market in order to commercialize our research results.

SummarySystemic lupus erythematosus (SLE) is a heterogeneous disease whereby an interplay of environmental, genetic and epigenetic factors lead to perturbation of complex biological networks culminating into diverse clinical phenotypes of varying severity. High throughput methods have allowed an “initial glimpse” into pathogenesis and have laid the foundations for a molecular-based taxonomy for personalized therapy. Based on our experience with the molecular characterization of SLE, a recently completed RNA sequencing analysis of 150 patients, and our track- record of “paradigm shift” trials in SLE, we will integrate data from multi-tissue analyses with novel technologies to improve its diagnosis, monitoring and therapy, and ask fundamental pathogenetic questions in systemic autoimmunity. More specifically, we will design gene expression panels and “expression profile”/”clinical trait” correlation matrices for diagnostics, personalized immunotherapy and improved clinical trial design. In a systematic multi-tissue approach, we will examine the role of somatic mutations in enhancing immune hyperactivity and the risk for lymphoma. The staggering (7-9:1) female predominance will be elucidated through elaborate genomic, epigenomic and microbiota analyses of family trios. Finally, we will be pursuing the innovative hypothesis that the fundamental abnormalities of SLE lie within the bone marrow hematopoietic stem cells (HSCs) - from which all cells that participate in the pathogenesis of SLE originate - and establish it as a unifying pathogenetic mechanism. By a combination of novel experimental analyses with single cell genomics, multi–omics, humanized animal models, genome editing and an “organ on-a-chip” device, we will validate HSCs as a therapeutic target. The utility of SLE research extends beyond its boundaries, by providing unique insights as to how the immune system recognizes self-constituents and maintains its homeostasis, and how gender impacts on disease biology.

Systemic lupus erythematosus (SLE) is a heterogeneous disease whereby an interplay of environmental, genetic and epigenetic factors lead to perturbation of complex biological networks culminating into diverse clinical phenotypes of varying severity. High throughput methods have allowed an “initial glimpse” into pathogenesis and have laid the foundations for a molecular-based taxonomy for personalized therapy. Based on our experience with the molecular characterization of SLE, a recently completed RNA sequencing analysis of 150 patients, and our track- record of “paradigm shift” trials in SLE, we will integrate data from multi-tissue analyses with novel technologies to improve its diagnosis, monitoring and therapy, and ask fundamental pathogenetic questions in systemic autoimmunity. More specifically, we will design gene expression panels and “expression profile”/”clinical trait” correlation matrices for diagnostics, personalized immunotherapy and improved clinical trial design. In a systematic multi-tissue approach, we will examine the role of somatic mutations in enhancing immune hyperactivity and the risk for lymphoma. The staggering (7-9:1) female predominance will be elucidated through elaborate genomic, epigenomic and microbiota analyses of family trios. Finally, we will be pursuing the innovative hypothesis that the fundamental abnormalities of SLE lie within the bone marrow hematopoietic stem cells (HSCs) - from which all cells that participate in the pathogenesis of SLE originate - and establish it as a unifying pathogenetic mechanism. By a combination of novel experimental analyses with single cell genomics, multi–omics, humanized animal models, genome editing and an “organ on-a-chip” device, we will validate HSCs as a therapeutic target. The utility of SLE research extends beyond its boundaries, by providing unique insights as to how the immune system recognizes self-constituents and maintains its homeostasis, and how gender impacts on disease biology.

SummaryBattling human neurodegenerative pathologies, and their pervasive societal impact, is a global multi-billion Euro enterprise. Ageing is universally associated with marked decrease of neuronal function and higher susceptibility to neurodegeneration. In human populations, this is manifested as an ever-increasing prevalence of devastating neurodegenerative conditions, including Alzheimer’s and Parkinson’s disease, stroke, several ataxias, and other types of dementia. Development of therapeutic interventions against such maladies is becoming a pressing priority. Drug discovery and drug target identification are two intimately linked facets of intervention strategies aimed at effectively combating human disorders. Genes linked to human diseases often function in evolutionary conserved pathways, readily dissected in simple model organisms. Such organisms provide attractive platforms for devising and streamlining efficient drug discovery and target identification methodologies. During the course of the ERC project NeuronAge, we developed a convenient and versatile platform for high-throughput chemical compound screening based on the nematode C. elegans (Nature 521: 525; Nature 490: 213). This innovative platform uniquely combines state-of-the-art microfluidics technologies for imaging and manipulation of neurons in vivo, with the experimental prowess of C. elegans, a highly malleable genetic model, which offers a precisely defined nervous system, two features that are not available in any other organism. We propose to: (1) bring this high-throughput compound screening system to pre-demonstration stage; (2) evaluate its dependability for drug target identification and drug discovery; (3) file US and European patent applications for IPR protection; and (4) identify potential commercialization opportunities. The overarching aim is to facilitate the exploitation of the innovation generated in the context of NeuronAge towards the betterment of human health and quality of life.

Battling human neurodegenerative pathologies, and their pervasive societal impact, is a global multi-billion Euro enterprise. Ageing is universally associated with marked decrease of neuronal function and higher susceptibility to neurodegeneration. In human populations, this is manifested as an ever-increasing prevalence of devastating neurodegenerative conditions, including Alzheimer’s and Parkinson’s disease, stroke, several ataxias, and other types of dementia. Development of therapeutic interventions against such maladies is becoming a pressing priority. Drug discovery and drug target identification are two intimately linked facets of intervention strategies aimed at effectively combating human disorders. Genes linked to human diseases often function in evolutionary conserved pathways, readily dissected in simple model organisms. Such organisms provide attractive platforms for devising and streamlining efficient drug discovery and target identification methodologies. During the course of the ERC project NeuronAge, we developed a convenient and versatile platform for high-throughput chemical compound screening based on the nematode C. elegans (Nature 521: 525; Nature 490: 213). This innovative platform uniquely combines state-of-the-art microfluidics technologies for imaging and manipulation of neurons in vivo, with the experimental prowess of C. elegans, a highly malleable genetic model, which offers a precisely defined nervous system, two features that are not available in any other organism. We propose to: (1) bring this high-throughput compound screening system to pre-demonstration stage; (2) evaluate its dependability for drug target identification and drug discovery; (3) file US and European patent applications for IPR protection; and (4) identify potential commercialization opportunities. The overarching aim is to facilitate the exploitation of the innovation generated in the context of NeuronAge towards the betterment of human health and quality of life.

Max ERC Funding

150 000 €

Duration

Start date: 2017-05-01, End date: 2018-10-31

Project acronymNEUROPHAGY

ProjectThe Role of Autophagy in Synaptic Plasticity

Researcher (PI)Vassiliki NIKOLETOPOULOU

Host Institution (HI)IDRYMA TECHNOLOGIAS KAI EREVNAS

Call DetailsStarting Grant (StG), LS5, ERC-2016-STG

SummaryNeuronal metabolism is emerging as an essential regulator of brain function and its deregulation is a common denominator in neurological disorders entailing intellectual disability and synapse dys-morphogenesis. The autophagy-lysosome system is the major catabolic pathway dedicated to the recycling not only of protein aggregates but also lipids, nucleic acids, polysaccharides and defective or superfluous organelles, among others.
Appreciation of the role of autophagic pathways in the healthy and diseased brain continues to expand, as accumulating evidence indicates that proper regulation of autophagy is indispensable for neuronal integrity. At the cellular level, several lines of evidence implicate autophagy in the regulation of synaptic plasticity. However, the synapse-specific substrates of autophagy remain elusive. Similarly, the synaptic defects arising from autophagy impairment have never been thus far systematically addressed, yet they translate into severe behavioural deficiencies, such as compromised memory and cognition, pertinent to disorders of intellectual disability.
The present proposal aims to determine how autophagy regulates synaptic plasticity and how its deregulation contributes to synaptic defects. In particular, the objectives aim to: 1) Monitor and characterize the presence of the autophagic machinery in pre- and post-synaptic sites. 2) Identify autophagic substrates residing in synapses and whose turnover via autophagy determines synaptic plasticity. 3) Characterize the synaptic defects and ensuing behavioural deficits arising from impaired autophagy in the hippocampus. 4) Use C. elegans as a model system to address the evolutionary conservation of the synaptic role of autophagy and perform forward genetic screens to reveal novel regulators of autophagy in synapses.

Neuronal metabolism is emerging as an essential regulator of brain function and its deregulation is a common denominator in neurological disorders entailing intellectual disability and synapse dys-morphogenesis. The autophagy-lysosome system is the major catabolic pathway dedicated to the recycling not only of protein aggregates but also lipids, nucleic acids, polysaccharides and defective or superfluous organelles, among others.
Appreciation of the role of autophagic pathways in the healthy and diseased brain continues to expand, as accumulating evidence indicates that proper regulation of autophagy is indispensable for neuronal integrity. At the cellular level, several lines of evidence implicate autophagy in the regulation of synaptic plasticity. However, the synapse-specific substrates of autophagy remain elusive. Similarly, the synaptic defects arising from autophagy impairment have never been thus far systematically addressed, yet they translate into severe behavioural deficiencies, such as compromised memory and cognition, pertinent to disorders of intellectual disability.
The present proposal aims to determine how autophagy regulates synaptic plasticity and how its deregulation contributes to synaptic defects. In particular, the objectives aim to: 1) Monitor and characterize the presence of the autophagic machinery in pre- and post-synaptic sites. 2) Identify autophagic substrates residing in synapses and whose turnover via autophagy determines synaptic plasticity. 3) Characterize the synaptic defects and ensuing behavioural deficits arising from impaired autophagy in the hippocampus. 4) Use C. elegans as a model system to address the evolutionary conservation of the synaptic role of autophagy and perform forward genetic screens to reveal novel regulators of autophagy in synapses.

Max ERC Funding

1 493 750 €

Duration

Start date: 2017-03-01, End date: 2022-02-28

Project acronymPyroTRACH

ProjectPyrogenic TRansformations Affecting Climate and Health

Researcher (PI)Athanasios NENES

Host Institution (HI)IDRYMA TECHNOLOGIAS KAI EREVNAS

Call DetailsConsolidator Grant (CoG), PE10, ERC-2016-COG

SummaryBiomass burning (BB) is a significant contributor to global atmospheric particulate matter, with strong impacts on climate, ecosystems and public health. Yet these impacts are highly uncertain, largely owing to our inability to track BB particulate matter and the evolution of their properties throughout most of its atmospheric lifetime. PyroTRACH will provide the necessary breakthroughs in our understanding of BB particles and their impacts by: i) deriving new markers of biomass burning with an atmospheric lifetime that exceeds the current limitation of about a day, ii) measuring highly uncertain but critically-important climate- and health- relevant properties of aerosols both from wildfire events that occur during summertime and from BB for heating purposes during wintertime in highly populated urban environments, iii) applying this new knowledge to quantify the contribution of biomass burning to aerosol in the Mediterranean region, and quantify its impacts on climate and public health. Novel state-of-the-art instrumentation, portable environmental chambers and well established measurement techniques will be applied in continuous measurements as well as intensive field campaigns to study the properties and evolution of BB particulates as they age in the atmosphere. Discovering new stable chemical markers that allow detection of BBOA many days after emission, while carefully and accurately following the climate and health-related properties of freshly emitted and aged BBOA, allows for an unprecedented understanding of the evolution and impacts of biomass burning aerosol and its impact on the Earth System and public health. Considering the increasing occurrence of wildfires, along with decreased emissions from fossil fuels means that accurately predicting the health and climate effects from biomass burning aerosol is one of the most important aspects of atmospheric aerosol that needs to be studied.

Biomass burning (BB) is a significant contributor to global atmospheric particulate matter, with strong impacts on climate, ecosystems and public health. Yet these impacts are highly uncertain, largely owing to our inability to track BB particulate matter and the evolution of their properties throughout most of its atmospheric lifetime. PyroTRACH will provide the necessary breakthroughs in our understanding of BB particles and their impacts by: i) deriving new markers of biomass burning with an atmospheric lifetime that exceeds the current limitation of about a day, ii) measuring highly uncertain but critically-important climate- and health- relevant properties of aerosols both from wildfire events that occur during summertime and from BB for heating purposes during wintertime in highly populated urban environments, iii) applying this new knowledge to quantify the contribution of biomass burning to aerosol in the Mediterranean region, and quantify its impacts on climate and public health. Novel state-of-the-art instrumentation, portable environmental chambers and well established measurement techniques will be applied in continuous measurements as well as intensive field campaigns to study the properties and evolution of BB particulates as they age in the atmosphere. Discovering new stable chemical markers that allow detection of BBOA many days after emission, while carefully and accurately following the climate and health-related properties of freshly emitted and aged BBOA, allows for an unprecedented understanding of the evolution and impacts of biomass burning aerosol and its impact on the Earth System and public health. Considering the increasing occurrence of wildfires, along with decreased emissions from fossil fuels means that accurately predicting the health and climate effects from biomass burning aerosol is one of the most important aspects of atmospheric aerosol that needs to be studied.